Activation of BMP Signaling by FKBP12 Ligands Synergizes with Inhibition of CXCR4 to Accelerate Wound Healing

Brandon J. Peiffer, Le Qi, Ali R. Ahmadi, Yuefan Wang, Zufeng Guo, Hanjing Peng, Zhao Li Sun, Jun Liu

Research output: Contribution to journalArticle

Abstract

The combination of AMD3100 and low-dose FK506 has been shown to accelerate wound healing in vivo. Although AMD3100 is known to work by releasing hematopoietic stem cells into circulation, the mechanism of FK506 in this setting has remained unknown. In this study, we investigated the activities of FK506 in human cells and a diabetic-rat wound model using a non-immunosuppressive FK506 analog named FKVP. While FKVP was incapable of inhibiting calcineurin, wound-healing enhancement with AMD3100 was unaffected. Further study showed that both FK506 and FKVP activate BMP signaling in multiple cell types through FKBP12 antagonism. Furthermore, selective inhibition of BMP signaling abolished stem cell recruitment and wound-healing enhancement by combination treatment. These results shed new light on the mechanism of action of FK506 in acceleration of wound healing, and raise the possibility that less toxic FKBP ligands such as FKVP can replace FK506 for the treatment of chronic wounds. Peiffer and colleagues report that a non-immunosuppressive FK506 analog (FKVP) significantly accelerates wound healing in diabetic rats when combined with AMD3100. FKVP was found to exert this FKBP12-specific effect through activation of the BMP pathway. Conversely, systemic BMP inhibition blocked treatment-enhanced healing and stem cell recruitment at wound areas.

Original languageEnglish (US)
Pages (from-to)652-661.e4
JournalCell Chemical Biology
Volume26
Issue number5
DOIs
StatePublished - May 16 2019

Keywords

  • AMD3100
  • bone morphogenic protein
  • FK506
  • FKBP
  • stem cells
  • wound healing

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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